Base-promoted cyclization of 3-alkynylquinoxaline-2-carbonitriles with CH-acids: A new method for the phenazine ring synthesis

Article abstract of DOI:10.1016/j.tet.2014.05.023

3-Alkynylquinoxaline-2-carbonitriles were directly transformed into 2,3-disubstituted phenazin-1-amines by treating with a CH-acid (diethylmalonate, ethyl cyanoacetate, malononitrile, 2-tosylacetonitrile, 2-(1-methyl-1H-benzo[d] imidazol-2-yl)acetonitrile, nitromethane) and t-BuOK in THF or DMSO. A new cascade process includes nucleophilic addition of a CH-acid carbanion to the CC bond of 3-alkynylquinoxaline-2-carbonitrile, 6-exo-dig cyclization of the intermediate allyl carbanion with the formation of 2,2-disubstituted 1-imino-1,2-dihydrophenazine and its aromatization via elimination of the C(2)-substituent. Several secondary reactions were also disclosed and discussed.

Full text of DOI:10.1016/j.tet.2014.05.023

Tetrahedron 70 (2014) 4617e4625
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base-promoted cyclization of 3-alkynylquinoxaline-2-carbonitriles
with CH-acids: a new method for the phenazine ring synthesis
*
Huong T.L. Nguyen, Anna V. Gulevskaya , Alexander F. Pozharskii,
Julia I. Nelina-Nemtseva
Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Alkynylquinoxaline-2-carbonitriles were directly transformed into 2,3-disubstituted phenazin-1-
Received 26 March 2014
Received in revised form 28 April 2014
Accepted 12 May 2014
amines by treating with
a CH-acid (diethylmalonate, ethyl cyanoacetate, malononitrile, 2-
tosylacetonitrile, 2-(1-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile, nitromethane) and t-BuOK in THF
or DMSO. A new cascade process includes nucleophilic addition of a CH-acid carbanion to the C^C bond
of 3-alkynylquinoxaline-2-carbonitrile, 6-exo-dig cyclization of the intermediate allyl carbanion with the
formation of 2,2-disubstituted 1-imino-1,2-dihydrophenazine and its aromatization via elimination of
the C(2)-substituent. Several secondary reactions were also disclosed and discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 16 May 2014
Keywords:
3-Alkynylquinoxaline-2-carbonitriles
Nucleophilic cyclization
Cascade cyclization
Phenazines
1. Introduction
strategies to enable the preparation of phenazines therefore re-
mains of major interest.
The phenazine nucleus is an integral component of many bi-
ologically active compounds, including more than 100 natural an-
tibiotics, produced by Pseudomonas, Streptomyces, marine, and
other microorganisms. Antibiotic, antitumor, antimalarial, and an-
tiparasitic properties of phenazines are well-documented.1 The
biological activity of phenazines is based on their ability for in-
tercalation, inhibition of topoisomerases and radical oxidation
processes, transfer of electrons in the process of methanogenesis
and so on.
Recently, we have reported that the reaction of 3-
alkynylquinoxaline-2-carbonitriles 1 with primary alkylamines in
the presence of a base proceeds via the tandem nucleophilic
addition to the C^C bondd6-exo-dig cyclization leading to the
formation of pyrido[3,4-b]quinoxalin-1(2H)-imines 2 (Scheme 1).2
From this we reasoned that analogous reaction of 3-
alkynylquinoxaline-2-carbonitriles 1 with the CH2-active com-
pounds as pronucleophiles could result in the formation of phena-
zine derivatives 3.
Until now, no general and effective method for the synthesis of
substituted phenazines1a has been reported. Commonly, sub-
stituents are introduced into the building blocks before phenazine
ring formation. The majority of the known methods have some
limitations due to the arrangement and the electronic nature of
substituents in the starting reagents. The low output of products
and rather harsh reaction conditions are other drawbacks in the
existing protocols. Currently, catalytic methods for phenazines
synthesis, based on the BuchwaldeHartwig and Ullmann reactions,
seem to be the most effective. However, the high cost of palladium
catalysts and their ligands is a limitation. The development of new
Scheme 1.
Herein, we wish to report on the results of this approach
allowing to synthesize 2,3-disubstituted phenazin-1-amines in
a simple and convenient way.
* Corresponding author. Tel.: þ7 863 297 5146; fax: þ7 863 297 5151; e-mail
addresses: agulevskaya@sfedu.ru, anvasgul@gmail.com (A.V. Gulevskaya).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.023

4618
H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
2. Results and discussion
malonate and 2 equiv t-BuOK led to an increase in the yields of
both products 5a and 6a (Table 1, entry 2). From the reaction
mixture a small amount of ethyl 6-cyano-10-oxo-8-phenyl-10H-
pyrido[1,2-a]quinoxaline-9-carboxylate 7a was also isolated. In
both cases the starting material 1a was partly recovered. In-
creasing the reaction time did not change the reaction output
significantly (Table 1, entry 3). In contrast, heating the reaction
mixture at 65 ꢀC changed the yields drastically (Table 1, entry 4);
diester 6a was a major product in this case, and only trace amount
of phenazine 5a was formed. The reaction of carbonitrile 1b with
diethyl malonate and t-BuOK at room temperature afforded
compounds 5b and 6b (Table 1, entry 5).
The starting 3-alkynylquinoxaline-2-carbonitriles
1
were
prepared from available 3-chloroquinoxaline-2-carbonitrile3
via the Sonogashira coupling in accordance with
a known
procedure.2
The treatment of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with diethyl malonate (1.2 equiv) and t-BuOK (1.2 equiv) in
dry THF at room temperature for 24 h gave a mixture of ethyl 1-
amino-3-phenylphenazine-2-carboxylate 5a and diethyl 2-
phenyl-1H-cyclopenta[b]quinoxaline-1,1-dicarboxylate 6a in 13
and 26% yields, respectively (Table 1, entry 1). The use of diethyl
Table 1
Reaction of 3-(arylethynyl)quinoxaline-2-carbonitriles 1 with CH2-active compounds in the presence of t-BuOK in THF
Entry
Starting compound
CH2XY
Reaction conditions
Yields, %
Recovered 1, %
X
Y
pKa (DMSO)4
equiv
1.2
1
2
1a
CO2Et
CO2Et
16.4
rt, 24 h
rt, 24 h
13 (5a)
26 (6a)
23 (5a)
29 (6a)
1 (7a)
24 (5a)
35 (6a)
3 (7a)
19
7
2
2
2
3
4
rt, 8 days
3
0
65 ꢀC, 48 h
Trace (5a)
59 (6a)
5 (7a)
5
6
7
1b
1a
1b
1a
1a
CO2Et
CN
CO2Et
CO2Et
CO2Et
CN
16.4
13.1
13.1
11.1
12.0
2
2
2
rt, 24 h
rt, 24 h
rt, 24 h
17 (5b)
33 (6b)
55 (5c)
4 (8)
36 (5d)
4 (7b)
64 (5c)
60 (5c)
34 (5c)
40 (5c)
19 (3ad)
24 (5e)
32
17
24
CN
8
9
10
11
CN
2
2
2
2
rt, 24 h
Trace
Trace
62
65 ꢀC, 7 h
rt, 24 h
CN
Tos
65 ꢀC, 11 h
trace
12
13
14
1a
CN
13.2 (H2O/acetone)5
2
2
2
rt, 48 h
25
5
65 ꢀC, 16 h
rt, 72 h
18 (5e)
18 (5f)
1b
CN
13.2 (H2O/acetone)5
34
15
16
1a
1b
NO2
NO2
H
H
17.2
17.2
2
2
rt, 48 h
rt, 72 h
6 (5g)
2 (5h)
78
86

H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
4619
The interaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with ethyl cyanoacetate afforded phenazine 5c as the main
product (55%) together with (Z)-ethyl 2-cyano-2-(9-cyano-10-oxo-
phenylpyrimido[4,5-a]phenazine-2,4(1H,3H)-dione 11 as the only
isolated product (Scheme 2).
8-phenyl-5H-pyrido[1,2-a]quinoxalin-6(10H)-ylidene)acetate
8
(Table 1, entry 6). The reaction of carbonitrile 1b with ethyl cya-
noacetate under the same conditions led to the formation of
phenazine 5d and pyridoquinoxaline 7b in 36 and 4% yields, re-
spectively (Table 1, entry 7).
When malonodinitrile was used as the CH-active compound,
the reaction selectively gave 1-amino-3-phenylphenazine-2-
carbonitrile 5c in 60e64% yield (Table 1, entries 8 and 9). Follow-
ing treatment with 2-tosylacetonitrile and t-BuOK at room tem-
perature, 3-(phenylethynyl)quinoxaline-2-carbonitrile 1a was also
transformed into compound 5c (Table 1, entry 10). Heating the
reaction mixture at 65 ꢀC led to an increase in yield of 5c and the
appearance of one more product, namely, 1-imino-3-phenyl-2-
tosyl-1,2-dihydrophenazine-2-carbonitrile 3ad (Table 1, entry 11).
The reactions of compounds 1a and 1b with 2-(1-methyl-1H-
benzo[d]imidazol-2-yl)acetonitrile in the presence of t-BuOK
afforded phenazine derivatives 5e and 5f, respectively, as the only
isolable products in 18e24% yield (Table 1, entries 12e14). Heating
the reaction mixture resulted in considerable tarring.
The interaction of compounds 1a,b with nitromethane pro-
duced only 2e6% of phenazines 5g,h (Table 1, entries 15 and 16).
The major part of the starting material in these experiments
was recovered. Reaction of 3-(phenylethynyl)quinoxaline-2-
carbonitrile 1a with 1,3-dimethylbarbituric acid and t-BuOK in
THF did not proceed, probably, because of the low solubility of 1a
salt in this solvent.
Scheme 2.
Phenazines 5aeh are red-colored compounds with lmax
478e497 nm and the end absorption ranging between 524 and
537 nm. Their mass spectra included the molecular peak ion, which
for 5a,c,d,g,h was the most intensive. The IR spectra of 5 indicated
the presence of NH2 group
3339e3378 cmꢁ1). In cases of 1-aminophenazines 5a,b the char-
acteristic nC
band at 1662e1684 cmꢁ1 was also registered. The
spectra of nitriles 5c,d included a nC
1H NMR spectra of 5cef in CDCl3 the protons of the amino group
resonated at 6.4e6.5 ppm as a broad singlet. The same peak for
compounds 5a,b,g,h was shifted to 7.4e7.5 ppm, apparently, due
to a weak chelation. In the spectra of 5a,deg the H(4) proton
appeared as a one-proton singlet at 7.3e7.7 ppm. The structures of
(
nas 3462e3482 cmꢁ1 and ns
]
O
^
N band at w2200 cmꢁ1. In the
d
d
d
5a and 5e were also proved by X-ray single crystal studies
(Figs. 1 and 2).
Products 6a and 8 were identical to authentic samples pre-
viously synthesized in our laboratory.6 The structures 3ad, 6b, 7, 10,
and 11 are supported by a combination of elemental analysis, mass
spectrometry, IR, 1H and 13C NMR spectroscopic measurements.
Plausible mechanisms for the formation of compounds 5e8 and
3 are depicted in Scheme 3. First, a CH-acid carbanion adds to one of
the triple bonds of 1 forming after a proton transfer an allyl carb-
anion 12. Further development of the process depends on the
substituents X and Y at the CH-acid termini. A competition of three
different pathways is responsible for the outcome.
We believed that low yields of phenazines 5g,h could be caused
by the low CH-acidity of nitromethane (Table 1). Therefore, to
achieve better result we tested other base/solvent systems for the
cyclization reaction. Refluxing carbonitrile 1a with a sixfold excess
of nitromethane in triethylamine did not improve the yield of
compound 5g (Table 2, entry 1). The use of DBU/acetonitrile system
had only a small positive impact on the phenazine 5g yield (Table 2,
entry 2). Besides, one more product, e.g., 3-phenylpyrido[4,3-b]
quinoxalin-1(2H)-one 10, has been isolated from the reaction
mixture. The use of t-BuOK base and DMSO solvent afforded
phenazine 5g in 36% yield (Table 2, entry 3); however, the reaction
was not selective producing also a comparable amount of 2-
(nitromethyl)-3-(phenylethynyl)quinoxaline 9.
Path A is the main and is realized as 6-exo-dig carbocyclization of
intermediate 12 producing imine 3. The latter loses one of the C(2)
substituents providing arylamide ion 14 and, after protonation,
Table 2
Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile 1a with nitromethane
Entry
CH3NO2 (equiv)
Base
Solvent
Reaction conditions
Yields, %
Recovered 1, %
1
2
6
3
Et3N
DBU
d
Reflux, 5 days
Reflux, 7 h
4 (5g)
9 (5g)
10 (10)
36 (5g)
29 (9)
66
Trace
MeCN
3
2
t-BuOK
DMSO
rt, 24 h
d
The t-BuOK/DMSO system was found to be more effective than
t-BuOK/THF for the interaction of 3-(phenylethynyl)quinoxaline-2-
carbonitrile 1a with malonodinitrile giving rise to phenazine 5c in
73% yield. Unfortunately, applying this base and solvent for reaction
of 1a with 1,3-dimethylbarbituric acid even at room temperature
led to the formation of complex mixture of products. At the same
time, heating 1a and 1,3-dimethylbarbituric acid with K2CO3 in
DMF proceeded rather unexpectedly yielding 3-methyl-5-
phenazine derivatives 5. Most likely, elimination of substituent Y
from imine 3 is assisted by the nucleophilic attack of tert-butoxide
ion. Indeed, in all cases the leaving group Y is more electrophilic
than the remaining group X (X¼CN, Y¼CO2Et, Tos; X¼1-methyl-1H-
benzo[d]imidazol-2-yl, Y¼CN; X¼NO2, Y¼H). A driving force for
this process is aromatization. Isolation of compound 3ad from the
reaction of 1a with 2-tosylacetonitrile is an additional argument in
favor of this mechanism.

4620
H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
Fig. 1. ORTEP plots for X-ray crystal structure of 5a.
Fig. 2. ORTEP plots for X-ray crystal structure of 5e.
Path B is an intramolecular nucleophilic aromatic substitution
Probably, the reaction of 1a with 1,3-dimethylbarbituric acid in
the presence of K2CO3 in DMF follows Path A producing initially the
spirocyclic imine 3ag (Scheme 4). However, the latter undergoes
intramolecular nucleophilic attack of the imine nitrogen atom on
the pyrimidine C(2)]O group resulting in the elimination of
a methylisocyanate molecule and annelation of the pyrimidine ring
to the phenazine system. The ability of 5,5-disubstituted and spi-
robarbituric acids to undergo the ring contraction is known.6,7
Nucleophilic reactions of potassium tert-butoxide have been also
reported.8
The formation of compound 10 can be rationalized as a result of
partial hydrolysis of the starting carbonitrile 1a to the corre-
sponding amide followed by a 6-endo-dig cyclization. We have
proved that this transformation proceeded on silica gel during flash
column chromatography of the reaction mixture. When a mixture
of 1a, DBU and acetonitrile (without nitromethane) was underwent
the same work-up, compound 10 was obtained as the only product
in 58% yield.
of the cyano group in the intermediate 12 leading to cyclopenta[b]
quinoxaline 6. This way is realized when diethyl malonate serves
as a CH2-active compound. As it is seen from Table 1, this CH-acid
has the greatest pKa value (excluding nitromethane). Therefore,
the corresponding carbanions 12aa and 12ba should be the most
nucleophilic in the series. Due to this, annelation of the cyclo-
pentane ring to the starting molecule 1 competes with the
phenazine ring formation. It seems that the cyclization of carb-
anion 12 into arylideneamide ion 13 is reversible. Comparing re-
actions of 1a with diethyl malonate carried out at room
temperature (Table 1, entry 2) and at 65 ꢀC (Table 1, entry 4), one
can assume that the formation of phenazine 5a (Path A) is kinet-
ically controlled whereas the cyclization of 1a into 6a (Path B) is
thermodynamically controlled.
Path C is based on an intramolecular acylation with participation
of the ring nitrogen atom and ethoxycarbonyl group of the in-
termediate 12. It is realized only with diethyl malonate and ethyl
cyanoacetate as CH-acids and produces pyridoquinoxaline de-
rivatives 7 and 8, the latter being a product of further substitution
of the cyano group with ethyl cyanoacetate residue in the molecule
7c (R¼Ph, X¼CN).
3. Conclusion
We have disclosed a simple and convenient method for the
synthesis of 2,3-disubstituted phenazin-1-amines via the cascade
interaction of 3-alkynylquinoxaline-2-carbonitriles with CH-acids
and potassium tert-butoxide in THF or DMSO. One of the advan-
tages of this method is mild reaction conditions. It is also obvious
Formation of 2-(nitromethyl)-3-(phenylethynyl)quinoxaline 9
in the reaction of 1a with nitromethane demonstrates one more
possibility, e.g., nucleophilic aromatic substitution of the cyano
group in the starting molecule with the CH-acid residue.

H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
4621
Scheme 3.
recorded on Varian Cary 50 Probe spectrophotometer in CHCl3.
Mass spectra were measured on a Finnigan MAT INCOS 50 spec-
trometer. CHN analysis was accomplished by combustion analysis
(Dumas and Pregl method). Melting points were determined in
glass capillaries using a Stuart SMP30 device and are uncorrected.
Flash column chromatography was performed on silica gel or Al2O3
(IIIeIV activity, Brockman). All commercial reagents were pur-
chased from Acros and Aldrich.
Scheme 4.
that the presence of the amino, cyano, and ethoxycarbonyl groups
in the synthesized phenazines allows further modification of these
molecules.
4.2. X-ray structure determination
Atomic coordinates, bond lengths, bond angles, and thermal
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC) and allocated the deposition numbers CCDC
993247 (5a) and CCDC 993248 (5e).
4. Experimental
4.1. General
4.3. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with diethylmalonate
Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker DPX-250 spectrometer (250 and
62.9 MHz, respectively). 1H and 13C NMR chemical shifts are in parts
per million (ppm) relative to Me4Si. Coupling constants are in hertz
(Hz). The IR spectra were recorded on an FT FSM-1202 spectrom-
eter (http://infraspek.ru) using Nujol. The UVevis spectra were
Diethyl malonate (160 mg, 0.15 mL, 1.0 mmol), t-BuOK (112 mg,
1.0 mmol), and dry THF (5 mL) were stirred for 30 min at room
temperature. To the resulting mixture 3-(phenylethynyl)quinoxa-
line-2-carbonitrile 1a (128 mg, 0.5 mmol) was added by portions.

4622
H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
The reaction mixture was stirred for 24 h at room temperature and
then evaporated to dryness without heating. The residue was
treated with several drops of acetic acid. After evaporation it was
mixed with silica gel and purified by flash column chromatography
on silica gel (3ꢂ40 cm) with CH2Cl2 as the eluent. The first fraction
was recovered 1a (9 mg, 7%). The red fraction with Rf 0.7 gave 5a
(39.5 mg, 23%). The yellow fraction with Rf 0.6 gave 7a (2 mg, 1%).
The yellowish fraction with Rf 0.4 gave 6a (56 mg, 29%).
128.2, 129.0, 129.6, 130.0, 130.2, 131.7, 135.2, 137.2, 140.8, 141.3,
144.8, 145.4, 146.3, 149.0, 169.6; IR, cmꢁ1: 1684 (C]O), 3361 and
3472 (NH2); UVevis, lmax (log ), nm: 319 (4.50), 364 sh (3.57), 450
3
(3.36), 486 (3.33), end absorption up to 535 nm; MS m/z: 357 ([Mþ],
33), 311 (28), 282 (17), 269 (18), 127 (7), 102 (11), 77 (14), 51 (8), 39
(8), 29 (100). Anal. Calcd for C22H19N3O2: C, 73.93; H, 5.36; N, 11.76.
Found: C, 73.81; H, 5.45; N, 11.91.
4.4.2. Diethyl 2-p-tolyl-1H-cyclopenta[b]quinoxaline-1,1-
4.3.1. Ethyl 1-amino-3-phenylphenazine-2-carboxylate 5a. Dark red
dicarboxylate 6b. Off-white needles with mp 130e131 ꢀC (hep-
needles with mp 164e165 ꢀC (heptane); 1H NMR (CDCl3)
d
ppm:
tane); 1H NMR (CDCl3)
d
ppm: 1.04 (t, J¼7.2 Hz, 6H, 2CH2CH3), 2.38
0.73 (t, J¼7.1 Hz, 3H, CH2CH3), 3.95 (q, J¼7.1 Hz, 2H, CH2CH3), 7.32
(s, 1H, H(4)), 7.34e7.45 (m, 7H, Ph and NH2), 7.73e7.86 (m, 2H, H(7)
and H(8)), 8.15e8.21 (m, 2H, H(6) and H(9)); 13C NMR (CDCl3)
(s, 3H, CH3), 4.04e4.26 (m, 4H, 2CH2CH3), 7.23 (d, J¼8.2 Hz, 2H,
p-Tol), 7.57 (s, 1H, H(3)), 7.65 (d, J¼8.2 Hz, 2H, p-Tol), 7.68e7.79 (m,
2H, H(6) and H(7)), 8.05 (dd, J¼8.1, 1.4 Hz, 1H, H(5) or H(8)), 8.16
d
ppm: 13.6, 60.7, 105.6, 117.3, 127.4, 128.3, 128.4, 129.6, 130.1, 130.2,
131.8, 135.2, 141.4, 143.8, 144.7, 145.4, 146.3, 149.2, 169.5; IR, cmꢁ1
1662 (C]O), 3339 and 3476 (NH2); UVevis, lmax (log ), nm: 320
(dd, J¼7.7, 1.8 Hz, 1H, H(8) or H(5)); 13C NMR (CDCl3)
d ppm: 14.2,
:
21.8, 63.0, 69.0, 128.1, 129.1, 129.2, 129.3, 129.8, 130.0, 130.2, 130.5,
3
140.6,140.9,143.1,154.5,157.3,157.9,166.3; IR, cmꢁ1: 1730 and 1764
(3.92), 365 sh (3.09), 450 (2.90), 481 (2.87), end absorption up to
534 nm; MS m/z: 343 ([Mþ], 100), 314 (7), 297 (93), 269 (57), 255
(51), 242 (12), 214 (6), 157 (8), 140 (15), 129 (7), 121 (11), 115 (16),
102 (11), 89 (5), 77 (20). Anal. Calcd for C21H17N3O2: C, 73.45; H,
4.99; N, 12.24. Found: C, 73.51; H, 5.07; N, 12.36.
(C]O); UVevis, lmax (log ), nm: 306 (4.50), 365 (4.76), 381 (4.75);
3
MS m/z: 402 ([M]þ, 18), 284 (41), 273 (12), 255 (20), 127 (9), 115 (6),
102 (7), 77 (7), 29 (100). Anal. Calcd for C24H22N2O4: C, 71.63; H,
5.51; N, 6.96. Found: C, 71.49; H, 5.35; N, 7.04.
4.5. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with ethyl cyanoacetate
4.3.2. Diethyl 2-phenyl-1H-cyclopenta[b]quinoxaline-1,1-
dicarboxylate 6a. Yellow solid with mp 120e122 ꢀC (heptane, lit.6
121e123 ꢀC); 1H NMR (CDCl3)
d
ppm: 1.03 (t, J¼7.1 Hz, 6H,
Ethyl cyanoacetate (160 mg, 0.15 mL,1.0 mmol), t-BuOK (112 mg,
1.0 mmol), and dry THF (5 mL) were stirred for 30 min at room
temperature. To the resulting mixture 3-(phenylethynyl)quinoxa-
line-2-carbonitrile 1a (128 mg, 0.5 mmol) was added by portions.
The reaction mixture was stirred for 24 h at room temperature and
filtered. The orange precipitate over the filter was rinsed with
diethyl ether. Then filtrate and precipitate were treated separately.
The orange precipitate was purified by flash column chroma-
tography on silica gel (3ꢂ30 cm) with CH2Cl2 as the eluent. The red
fraction with Rf 0.7 gave 5c (65 mg, 44%). The next orange fraction
with Rf 0.6 gave 8 (6 mg, 3%).
2CH2CH3), 4.04e4.26 (m, 4H, 2CH2CH3), 7.41e7.45 (m, 3H, Ph), 7.63
(s, 1H, H(3)), 7.65e7.78 (m, 4H, Ph, H(6) and H(7)), 8.07 (dd, J¼8.2,
1.6 Hz,1H, H(5) or H(8)), 8.17 (dd, J¼7.9,1.9 Hz,1H, H(8) or H(5)); 13
C
NMR (CDCl3) d ppm: 14.1, 63.0, 69.1, 128.1, 129.0, 129.2, 129.3, 130.2,
130.3, 130.5, 130.6, 132.8, 140.7, 143.1, 154.4, 157.2, 157.6, 166.2; IR,
cmꢁ1: 1730 and 1770 (C]O); UVevis, lmax (log
), nm: 290 (4.25),
3
360 (4.19), 375 (4.22), 405 (4.08), 425 (4.11); MS m/z: 388 ([M]þ, 24),
287 (6), 270 (100), 259 (26), 243 (38), 229 (11), 214 (16), 152 (6), 140
(33), 129 (12), 115 (54), 102 (36), 88 (20), 77 (41). Anal. Calcd for
C
23H20N2O4: C, 71.12; H, 5.19; N, 7.21. Found:C, 70.91; H, 5.36;N, 7.28.
The filtrate was evaporated to dryness without heating. The
residue was treated with several drops of acetic acid. After evapo-
ration it was mixed with silica gel and purified by flash column
chromatography on silica gel (3ꢂ30 cm) with CH2Cl2 as the eluent.
The first fraction was recovered 1a (22 mg, 17%). The red fraction
with Rf 0.7 gave 5c (16 mg,11%). The orange fraction with Rf 0.6 gave
8 (2 mg, 1%).
4.3.3. Ethyl
line-9-carboxylate 7a. Yellow solid with mp 186e187 ꢀC (heptane);
1H NMR (CDCl3)
6-cyano-10-oxo-8-phenyl-10H-pyrido[1,2-a]quinoxa-
d
ppm: 1.10 (t, J¼7.1 Hz, 3H, CH2CH3), 4.23
(q, J¼7.1 Hz, 2H, CH2CH3), 7.32 (s, 1H, H(7)), 7.46e7.55 (m, 5H, Ph),
7.61e7.76 (m, 2H, H(2) and H(3)), 7.95 (dd, J¼7.7, 1.9 Hz, 1H, H(4)),
9.91 (dd, J¼8.7, 1.4 Hz, 1H, H(1)); 13C NMR (CDCl3)
d ppm: 14.2, 62.5,
109.0,109.2,114.0,127.2,128.3,129.0,129.1,129.5,130.5,131.5,132.6,
133.4, 135.1, 136.1, 136.7, 148.7, 160.1, 165.7; IR, cmꢁ1: 1652 and 1731
4.5.1. 1-Amino-3-phenylphenazine-2-carbonitrile
5c. Red-orange
ppm: 6.40
(C]O), 2234 (C^N); UVevis, lmax (log
3
), nm: 293 (3.66), 314 (3.63),
needles with mp 264e265 ꢀC (MeCN); 1H NMR (CDCl3)
d
440 (3.48); MS m/z: 369 ([Mþ], 15), 296 (10), 269 (88), 140 (21), 113
(11),102 (19), 76 (16), 29 (100). Anal. Calcd for C22H15N3O3: C, 71.54;
H, 4.09; N, 11.38. Found: C, 71.69; H, 3.92; N, 11.54.
(brs, 2H, NH2), 7.48e7.57 (m, 4H, Ph and H(4)), 7.69e7.73 (m, 2H, Ph),
7.81e7.95 (m, 2H, H(7) and H(8)), 8.22e8.28 (m, 2H, H(6) and H(9));
13C NMR (pyridine-d5)
d
ppm: 87.7, 116.3, 118.7, 129.2, 129.3, 129.5,
129.9,130.2,130.7,132.3,134.3,139.8,141.6,145.0,145.4,145.7,153.6;
IR, cmꢁ1: 2201 (C^N), 3378 and 3482 (NH2); UVevis, lmax (log
),
4.4. Reaction of 3-(p-tolylethynyl)quinoxaline-2-carbonitrile
3
1b with diethylmalonate
nm: 314 (3.93), 364 sh (2.96), 385 sh (2.84), 445 (2.80), 479 (2.68),
end absorption up to 534 nm; MS m/z: 296 ([Mþ], 100), 268 (9), 168
(9), 148 (9), 140 (8), 134 (6), 121 (7), 102 (9), 77 (12). Anal. Calcd for
The reaction was carried out similarly to the described above.
The separation of the reaction products was carried out by flash
column chromatography on silica gel (3ꢂ30 cm) with CH2Cl2 as the
eluent. The first fraction recovered with Rf 0.7 was 1b (43 mg, 32%).
The red fraction with Rf 0.4 gave 5b (31 mg, 17%). The yellowish
fraction with Rf 0.2 gave 6b (67 mg, 33%).
C19H12N4: C, 77.01; H, 4.08; N,18.91. Found: C, 77.13; H, 4.28; N,18.77.
4.5.2. (Z)-Ethyl 2-cyano-2-(9-cyano-10-oxo-8-phenyl-5H-pyrido
[1,2-a]quinoxalin-6(10H)-ylidene)acetate 8. Orange needles with
mp 218e220 ꢀC (CH2Cl2/EtOH, 100:1 v/v; lit.6 218e220 ꢀC); 1H NMR
(CDCl3)
d
ppm: 1.40 (t, J¼7.2 Hz, 3H, CH2CH3), 4.38 (q, J¼7.2 Hz, 2H,
4.4.1. Ethyl 1-amino-3-p-tolylphenazine-2-carboxylate 5b. Dark red
CH2CH3), 7.20e7.25 (m, 1H, Harom), 7.28e7.35 (m, 1H, Harom),
7.39e7.45 (m, 1H, Harom), 7.56e7.58 (m, 3H, Harom), 7.83e7.87
(m, 2H, Harom), 8.33 (s, 1H, H(7)), 9.31 (d, J¼8.5 Hz, 1H, H(1)), 13.54
needles with mp 151e152 ꢀC (heptane); 1H NMR (CDCl3)
d ppm:
0.77 (t, J¼7.1 Hz, 3H, CH2CH3), 2.40 (s, 3H, CH3), 3.97 (q, J¼7.1 Hz,
2H, CH2CH3), 7.21 (d, J¼7.8 Hz, 2H, p-Tol), 7.31e7.40 (m, 5H, H(4),
p-Tol and NH2), 7.73e7.86 (m, 2H, H(7) and H(8)), 8.15e8.21 (m, 2H,
(br s, 1H, NH); 13C NMR (CDCl3)
d ppm: 14.6, 62.8, 71.9, 106.5, 111.6,
115.3, 117.9, 118.5, 121.6, 125.0, 126.1, 126.7, 129.1, 129.3, 129.9, 132.3,
H(6) and H(9)); 13C NMR (CDCl3)
d
ppm: 13.6, 21.6, 60.8, 105.9, 117.1,
133.8, 134.3, 150.8, 156.5, 160.7, 169.9; IR, cmꢁ1: 1648 and 1662 (C]

H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
4623
O), 2206 (C^N), 3000e3500 (NeH); UVevis, lmax (log
3
), nm: 242
quinoxaline-2-carbonitrile 1a (128 mg, 0.5 mmol) was added by
portions. The reaction mixture was stirred for 11 h at 65 ꢀC and then
evaporated to dryness without heating. The residue was treated
with some drops of acetic acid. After evaporation it was mixed with
silica gel and purified by flash column chromatography on silica gel
(3ꢂ40 cm) with CH2Cl2 as the eluent. The first fraction recovered
was 1a (trace). The red fraction with Rf 0.7 gave 5c (59 mg, 40%). The
yellow fraction with Rf 0.1 gave 3ad (43 mg, 19%).
(4.23), 260 (4.25), 327 (4.14), 422 (4.10), 485 sh (3.75); MS m/z: 408
([M]þ, 46), 362 (100), 334 (39), 305 (31), 280 (17), 269 (7), 253 (5),
235 (14), 209 (6), 169 (7), 153 (11), 140 (33), 127 (8), 113 (16), 102
(33), 88 (9), 77 (49). Anal. Calcd for C24H16N4O3: C, 70.58; H, 3.95; N,
13.72. Found: C, 70.72; H, 4.13; N, 13.89.
4.6. Reaction of 3-(p-tolylethynyl)quinoxaline-2-carbonitrile
1b with ethyl cyanoacetate
4.8.1. 1-Imino-3-phenyl-2-tosyl-1,2-dihydrophenazine-2-carbonitrile
The reaction was carried out similarly to the described in Section
4.5. The separation of the reaction products was carried out by flash
column chromatography on silica gel (2.5ꢂ60 cm) with CHCl3 as
the eluent. The first fraction with Rf 0.5 was recovered 1b (32 mg,
24%). The red fraction with Rf 0.2 gave 5d (56 mg, 36%). The yel-
lowish fraction with Rf 0.1 gave 7b (7 mg, 4%).
3ad. Yellow solid with mp 319e320 ꢀC (i-PrOH); 1H NMR (CDCl3)
d
ppm: 2.30 (s, 3H, Me), 6.70 (br s, 1H, NH), 7.21 (d, J¼8.2 Hz, 2H,
Tos), 7.45e7.60 (m, 5H, Ph), 7.82e7.96 (m, 2H, H(7) and H(8)), 8.08
(d, J¼8.2 Hz, 2H, Tos), 8.12e8.23 (m, 2H, H(6) and H(9)); 13C NMR
(DMSO-d6)
d ppm: 21.8, 90.1, 116.7, 121.1, 128.5, 128.7, 128.9, 129.2,
129.5, 129.6, 130.2, 132.7, 133.1, 134.3, 139.0, 140.6, 141.5, 141.8,
143.6, 143.7, 150.9, 155.1; IR (KBr), cmꢁ1: 1150 (SO2, s), 1319 (SO2,
4.6.1. 1-Amino-3-p-tolylphenazine-2-carbonitrile
5d. Red-orange
ppm: 2.43
as), 2214 (C^N), 3311 (NH); UVevis, lmax (log ), nm: 304 (4.02),
3
needles with mp 267e268 ꢀC (i-PrOH); 1H NMR (CDCl3)
d
353 (3.41), 366 (3.32), 437 (3.28), 486 sh (2.87); MS m/z: 295 (33,
[MꢁTos]þ), 294 (27, [MꢁTosH]þ), 293 (34, [MꢁTosH2]þ), 139 (16),
91 (78), 89 (15), 77 (36), 65 (100). Anal. Calcd for C26H18N4O2S: C,
69.32; H, 4.03; N, 12.44; S, 7.12. Found: C, 69.47; H, 3.88; N, 12.51.
(s, 3H, CH3), 6.35 (br s, 2H, NH2), 7.28 (d, J¼8.0 Hz, 2H, p-Tol), 7.35 (s,
1H, H(4)), 7.61 (d, J¼8.0 Hz, 2H, p-Tol), 7.79e7.91 (m, 2H, H(7) and
H(8)), 8.18e8.24 (m, 2H, H(6) and H(9)); 13C NMR (pyridine-d5)
d
ppm: 21.3, 87.9, 116.0, 118.8, 129.4, 129.8, 129.9, 130.2, 130.7, 132.3,
134.3, 136.9, 139.1, 141.5, 145.1, 145.5, 145.7, 153.6; IR, cmꢁ1: 2202
(C^N), 3372 and 3478 (NH2); UVevis, lmax (log ), nm: 316 (4.29),
4.9. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with 2-(1-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile
3
369 sh (3.35), 387 sh (3.25), 444 (3.18), 478 (3.06), end absorption up
to 534 nm; MS m/z: 310 ([Mþ], 100). Anal. Calcd for C20H14N4: C,
77.40; H, 4.55; N, 18.05. Found: C, 77.22; H, 4.38; N, 17.93.
2-(1-Methyl-1H-benzo[d]imidazol-2-yl)acetonitrile (171 mg,
1.0 mmol), t-BuOK (112 mg, 1.0 mmol), and dry THF (5 mL) were
stirred for 30 min at room temperature. To the resulting mix-
ture 3-(phenylethynyl)quinoxaline-2-carbonitrile 1a (128 mg,
0.5 mmol) was added by portions. The reaction mixture was
stirred for 48 h at room temperature and then evaporated to
dryness without heating. The residue was treated with some drops
of acetic acid. After evaporation it was mixed with silica gel and
purified by flash column chromatography on silica gel (2.5ꢂ40 cm)
with CHCl3 as the eluent. The first fraction recovered was 1a
(32 mg, 25%). The orange fraction was collected and purified ad-
ditionally by flash column chromatography on Al2O3 (2.5ꢂ20 cm)
with CHCl3 as the eluent. The orange red fraction with Rf 0.65 gave
5e (48 mg, 24%).
4.6.2. 10-Oxo-8-p-tolyl-10H-pyrido[1,2-a]quinoxaline-6,9-
dicarbonitrile 7b. Yellow solid with mp 298e299 ꢀC (i-PrOH); 1H
NMR (CDCl3)
d
ppm: 2.46 (s, 3H, CH3), 7.37 (d, J¼0.8 Hz, 1H, H(7)),
7.40 (d, J¼8.2 Hz, 2H, p-Tol), 7.67 (d, J¼8.2 Hz, 2HH, p-Tol), 7.72e7.75
(m, 1H, H(3)), 7.78e7.86 (m, 1H, H(2)), 8.01 (dd, J¼7.8, 1.7 Hz, 1H,
H(4)), 9.88 (dm, J¼8.8 Hz, 1H, H(1)); 13C NMR (CDCl3)
d ppm: 22.0,
107.8, 113.7, 115.6, 121.8, 128.1, 128.8, 128.9, 129.7, 130.5, 130.6, 131.6,
131.8, 134.2, 134.5, 134.6, 137.0, 142.9, 157.1; IR (KBr), cmꢁ1: 1673
(C¼O), 2223 (C^N); UVevis, lmax (log
3
), nm: 280 (3.89), 309
(3.82), 342 (3.72), 431 sh (3.56), 456 (3.65), 481 sh (3.52); MS m/z:
336 ([M]þ, 100), 308 (72), 292 (6), 168 (6), 154 (11), 140 (10), 127
(12), 102 (10), 76 (9). Anal. Calcd for C21H12N4O: C, 74.99; H, 3.60; N,
16.66. Found: C, 75.13; H, 3.45; N, 16.83.
4.9.1. 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)-3-phenylphenazin-1-
amine 5e. Red solid with mp 199e200 ꢀC (heptane); 1H NMR
4.7. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with malonodinitrile
(CDCl3)
(m, 8H, Harom), 7.70 (s, 1H, H(4)), 7.76e7.91 (m, 3H, Harom),
8.21e8.26 (m, 2H, H(6) and H(9)); 13C NMR (CDCl3)
ppm: 31.0,
d ppm: 3.02 (s, 3H, CH3), 6.47 (br s, 2H, NH2), 7.14e7.42
d
Malonodinitrile (66 mg, 1.0 mmol), t-BuOK (112 mg, 1.0 mmol),
and dry THF (5 mL) were stirred for 30 min at room temperature. To
the resulting mixture 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a (128 mg, 0.5 mmol) was added by portions. The reaction mix-
ture was stirred for 24 h at room temperature and then evaporated
to dryness without heating. The residue was treated with some
drops of acetic acid. After evaporation it was mixed with Al2O3 and
purified by flash column chromatography on Al2O3 (2ꢂ40 cm) with
CH2Cl2 as the eluent. The first fraction recovered was 1a (trace). The
red fraction with Rf 0.4 gave 5c (95 mg, 64%).
106.2,110.0,116.9,119.9,122.8,123.1,128.3,128.9,129.1,129.7,130.2,
130.3, 131.5, 135.0, 135.6, 140.7, 141.8, 143.4, 144.5, 145.1, 145.4,
146.8, 151.6; IR (KBr), cmꢁ1: 3374 and 3477 (NH2); UVevis, lmax
(log ), nm: 321 (4.14), 380 sh (3.42), 439 (3.12), 486 (3.06), end
3
absorption up to 524 nm; MS m/z: 401 ([Mþ], 9), 384 (7), 282 (20),
201 (15),192 (14),140 (14),119 (14),102 (39), 92 (17), 77 (100). Anal.
Calcd for C26H19N5: C, 77.79; H, 4.77; N, 17.44. Found: C, 77.64; H,
4.95; N, 17.36.
4.10. Reaction of 3-(p-tolylethynyl)quinoxaline-2-carbonitrile
1b with 2-(1-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile
Reaction of 1a (128 mg, 0.5 mmol) with malonodinitrile (66 mg,
1.0 mmol), t-BuOK (112 mg, 1.0 mmol), and dry DMSO (5 mL) was
carried out similarly.
The reaction was carried out similarly to the above reaction with
2-(1-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile
(171
mg,
4.8. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with 2-tosylacetonitrile
1.0 mmol), t-BuOK (112 mg, 1.0 mmol), dry THF (5 mL), and 3-(p-
tolylethynyl)quinoxaline-2-carbonitrile 1b (135 mg, 0.5 mmol) for
72 h at room temperature.
2-Tosylacetonitrile (195 mg, 1.0 mmol), t-BuOK (112 mg,
1.0 mmol), and dry THF (5 mL) were stirred for 30 min at room
temperature. To the resulting mixture 3-(phenylethynyl)
4.10.1. 2-(1-Methyl-1H-benzo[d]imidazol-2-yl)-3-p-tolylphenazin-1-
amine 5f. Red solid with mp 282e283 ꢀC (heptane); 1H NMR

4624
H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
(CDCl3)
d
ppm: 2.27 (s, 3H, CH3), 3.05 (s, 3H, CH3), 6.46 (br s, 2H,
1354 and 1556 (NO2), 2212 (C^C), 2931 (CeH); UVevis, lmax (log ),
3
NH2), 7.01 (d, J¼8.0 Hz, 2H, p-Tol), 7.16e7.38 (m, 5H, Harom), 7.67
nm: 292 (4.16), 352 (4.06), 362 (4.03), 436 (3.04), 490 (2.69); MS m/
z: 289 ([Mþ], 6), 259 (28), 243 ([MꢁNO2]þ, 73), 127 (9), 121 (15), 115
(100), 89 (24), 76 (15). Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83;
N, 14.53. Found: C, 70.40; H, 3.72; N, 14.45.
(s, 1H, H(4)), 7.75e7.91 (m, 3H, Harom), 8.20e8.25 (m, 2H, H(6) and
H(9)); 13C NMR (CDCl3)
d ppm: 21.6, 31.0, 106.3, 110.1, 116.7, 119.9,
122.7, 123.0, 124.6, 128.9, 129.7, 130.1, 130.3, 131.5, 135.0, 135.6,
137.8, 138.2, 141.7, 143.4, 144.6, 145.1, 145.4, 146.7, 151.8; IR (KBr),
cmꢁ1: 3364 and 3478 (NH2); UVevis, lmax (log
3 ), nm: 328 (3.78),
4.11.3. 3-Phenylpyrido[4,3-b]quinoxalin-1(2H)-one 10. Yellow nee-
391 (3.21), 438 (3.07), 490 (2.85), end absorption up to 524 nm; MS
m/z: 415 ([Mþ], 4), 208 (11), 200 (12), 119 (15), 115 (12), 102 (42), 91
(23), 77 (100). Anal. Calcd for C27H21N5: C, 78.05; H, 5.09; N, 16.86.
Found: C, 78.16; H, 5.29; N, 16.70.
dles decomp. >310 ꢀC (EtOH); 1H NMR (DMSO-d6)
d ppm: 7.09 (s,
1H, H(4)), 7.33e7.53 (m, 3H, Ph), 7.79 (d, J¼7.4 Hz, 2H, Ph),
7.95e8.07 (m, 2H, H(7) and H(8)), 8.25e8.37 (m, 2H, H(6) and
H(9)); 13C NMR (DMSO-d6)
d
ppm: 107.6, 128.6, 129.3, 129.4, 129.8,
130.2, 131.0, 131.2, 132.8, 134.0, 142.8, 143.3, 143.6, 149.9, 165.0; IR
(KBr), cmꢁ1: 1725 (C]O), 3238 (NeH); UVevis (MeCN), lmax (log
),
4.11. Reaction of 3-(phenylethynyl)quinoxaline-2-carbonitrile
1a with nitromethane
3
nm: 321 (4.13), 346 sh (3.91), 402 (3.41), 442 sh (3.30), 483 (2.93);
MS m/z: 273 ([Mþ], 84), 272 (100), 244 (11), 116 (13), 102 (16), 89
(25), 76 (7). Anal. Calcd for C17H11N3O: C, 74.71; H, 4.06; N, 15.38.
Found: C, 74.87; H, 3.97; N, 15.54.
Method A: Nitromethane (61 mg, 0.054 mL, 1.0 mmol), t-BuOK
(112 mg, 1.0 mmol), and dry THF (5 mL) were stirred for 30 min at
room temperature. To the resulted mixture 3-(phenylethynyl)qui-
noxaline-2-carbonitrile 1a (128 mg, 0.5 mmol) was added by por-
4.12. Reaction of 3-(p-tolylethynyl)quinoxaline-2-carbonitrile
1b with nitromethane
tions. The reaction mixture was stirred for 48
h at room
temperature and then evaporated to dryness without heating. The
residue was treated with some drops of acetic acid. After evapo-
ration it was mixed with silica gel and purified by flash column
chromatography on silica gel (2.5ꢂ40 cm) with CHCl3 as the eluent.
The first fraction recovered was 1a (99 mg, 78%). The orange frac-
tion with Rf 0.2 gave 5g (9 mg, 6%).
Method B: The reaction of 1a (128 mg, 0.5 mmol) with nitro-
methane (61 mg, 0.054 mL, 1.0 mmol), t-BuOK (112 mg, 1.0 mmol),
and dry DMSO (3 mL) was carried out similarly for 24 h at room
temperature. The reaction mixture was diluted with saturated
solution of NH4Cl (50 mL) and extracted with CHCl3 (6ꢂ30 mL). The
extract was evaporated to dryness under reduced pressure. The
residue was mixed with silica gel and purified by flash column
chromatography on silica gel (2.5ꢂ60 cm) with CH2Cl2 as the
eluent. The yellow fraction with Rf 0.7 gave 9 (42 mg, 29%). The next
orange fraction gave 5g (57 mg, 36%).
Method C: A mixture of 1a (128 mg, 0.5 mmol), nitromethane
(92 mg, 0.081 mL, 1.5 mmol), DBU (228 mg, 1.5 mmol), and dry
acetonitrile (5 mL) was stirred under reflux for 7 h. The reaction
mixture was then evaporated to dryness without heating. The
residue was treated with some drops of acetic acid. After evapo-
ration it was mixed with silica gel and purified by flash column
chromatography on silica gel (2.5ꢂ40 cm) with CH2Cl2 as the
eluent. The first fraction recovered was 1a (2 mg). The orange
fraction with Rf 0.5 gave 5g (15 mg, 9%). The yellowish fraction with
Rf 0.1 gave 10 (14 mg, 10%).
The reaction was carried out similarly to the above reaction with
3-(p-tolylethynyl)quinoxaline-2-carbonitrile
1b
(135
mg,
0.5 mmol) for 72 h at room temperature.
4.12.1. 2-Nitro-3-p-tolylphenazin-1-amine 5h. Red-orange solid
with mp 233e234 ꢀC (heptane/ethanol, 10:1 v/v); 1H NMR
(CDCl3)
d
ppm: 2.41 (s, 3H, CH3), 7.27 (d, J¼8.0 Hz, 2H, p-Tol),
7.32e7.37 (m, 3H, p-Tol and H(4)), 7.64 (br s, 2H, NH2), 7.81e7.95
(m, 2H, H(7) and H(8)), 8.17e8.24 (m, 2H, H(6) and H(9)); 13C
NMR (CDCl3)
131.1, 132.7, 135.3, 136.9, 138.3, 141.0, 141.4, 143.9, 144.6, 145.8; IR
(KBr), cmꢁ1: 3351 and 3462 (NH2); UVevis, lmax (log
), nm: 276
d ppm: 21.7, 118.6, 127.5, 127.6, 129.8, 129.9, 130.1,
3
(4.09), 356 (3.95), 406 sh (3.51), 454 sh (3.16), 497 sh (3.02), end
absorption up to 537 nm; MS m/z: 330 ([Mþ], 100), 313 (27), 300
(14), 285 (22), 269 (20), 256 (10), 246 (8), 232 (13), 193 (9), 140
(10), 128 (14), 115 (15), 102 (16), 77 (17). Anal. Calcd for
C
19H14N4O2: C, 69.08; H, 4.27; N, 16.96. Found: C, 68.89; H, 4.15;
N, 16.78.
4.13. Reaction of 3-(phenylethynyl)quinoxaline-2-
carbonitrile 1a with 1,3-barbituric acid
1,3-Barbituric acid (94 mg, 0.6 mmol), K2CO3 (83 mg, 0.6 mmol),
and dry DMF (5 mL) were stirred for 30 min at 80 ꢀC. To the
resulting mixture 3-(phenylethynyl)quinoxaline-2-carbonitrile 1a
(128 mg, 0.5 mmol) was added by portions. The reaction mixture
was stirred for 30 h at 80 ꢀC and then treated with saturated
aqueous solution of NH4Cl (50 mL). The resulted mixture was
extracted with CHCl3 (5ꢂ20 mL). The extract was dried over Na2SO4
and evaporated to dryness. The residue was mixed with silica gel
and purified by flash column chromatography on silica gel
(2.5ꢂ30 cm) with CHCl3 as the eluent. The yellowish fraction with
Rf 0.1 gave 11 (7 mg, 4%).
4.11.1. 2-Nitro-3-phenylphenazin-1-amine 5g. Red-orange solid
with mp 216e217 ꢀC (heptane/ethanol, 10:1 v/v); 1H NMR (CDCl3)
d
ppm: 7.34 (s, 1H, H(4)), 7.38e7.48 (m, 5H, Ph), 7.71 (br s, 2H, NH2),
7.82e7.95 (m, 2H, H(7) and H(8)), 8.20e8.26 (m, 2H, H(6) and H(9));
13C NMR (CDCl3)
ppm: 118.9, 127.6, 128.4, 129.0, 129.1, 129.9, 130.1,
131.2, 132.8, 135.4, 139.9, 141.0, 141.5, 144.1, 144.6, 145.8; IR (KBr),
cmꢁ1: 3350 and 3462 (NH2); UVevis, lmax (log
), nm: 275 (4.06),
d
3
352 (3.91), 398 sh (3.44), 447 sh (3.01), 485 sh (2.84), end ab-
sorption up to 533 nm; MS m/z: 316 ([Mþ], 100), 299 (18), 259 (27),
286 (11), 270 (23), 258 (7), 243 (10), 193 (6), 140 (7), 115 (11), 102
(11), 77 (14). Anal. Calcd for C18H12N4O2: C, 68.35; H, 3.82; N, 17.71.
Found: C, 68.49; H, 4.00; N, 17.57.
4.13.1. 3-Methyl-5-phenylpyrimido[4,5-a]phenazine-2,4(1H,3H)-di-
one 11. Yellow solid with mp 252e253 ꢀC (i-PrOH); 1H NMR
(CDCl3)
H(6)), 7.89e8.00 (m, 2H, H(9) and H(10)), 8.26e8.31 (m, 2H, H(8)
and H(11)), 10.02 (br s, 1H, NH); 13C NMR (pyridine-d5)
ppm: 27.8,
d ppm: 3.43 (s, 3H, CH3), 7.40e7.49 (m, 5H, Ph), 7.77 (s, 1H,
4.11.2. 2-(Nitromethyl)-3-(phenylethynyl)quinoxaline 9. Beige solid
d
with mp 173e174 ꢀC (hexane); 1H NMR (CDCl3)
d
ppm: 6.14 (s, 2H,
110.1, 125.2, 127.8, 128.1, 129.5, 129.9, 130.3, 131.7, 132.8, 133.5, 141.0,
CH2), 7.44e7.55 (m, 3H, Ph), 7.71 (dd, J¼7.6, 1.9 Hz, 2H, Ph),
142.2, 142.4, 144.4, 144.5, 145.8, 158.7, 161.7; IR (KBr), cmꢁ1: 1668
7.86e7.97 (m, 2H, H(6) and H(7)), 8.16e8.23 (m, 2H, H(5) and H(8));
and 1674 (C]O); UVevis, lmax (log ), nm: 301 (3.98), 356 (3.31),
3
13C NMR (CDCl3)
d
ppm: 78.9, 84.7, 97.5, 120.7, 128.7, 129.1, 129.5,
366 (3.29), 428 (3.13); MS m/z: 354 ([M]þ, 32), 297 (10), 269 (43),
130.3, 131.3, 131.9, 132.4, 139.3, 140.3, 142.2, 145.6; IR (KBr), cmꢁ1
:
255 (41), 177 (32), 165 (11), 140 (62), 127 (11), 114 (51), 102 (94), 88

H.T.L. Nguyen et al. / Tetrahedron 70 (2014) 4617e4625
4625
(29), 77 (100). Anal. Calcd for C21H14N4O2: C, 71.18; H, 3.98; N, 15.81.
References and notes
Found: C, 71.03; H, 4.15; N, 15.98.
1. (a) Laursen, J. B.; Nielsen, J. Chem. Rev. 2004, 104, 1663e1685; (b) Mavrodi, D.
V.; Blankenfeldt, W.; Thomashow, L. S. Annu. Rev. Phytopathol. 2006, 44,
417e445; (c) Pierson, L. S.; Pierson, E. A. Appl. Microbiol. Biotechnol. 2010, 86,
1659e1670; (d) Mavrodi, D. V.; Pareiko, J. A.; Mavrodi, O. V.; Kwak, Y.-S.;
Weller, D. M.; Blankenfeldt, W.; Thomashow, L. S. Environ. Microbiol. 2013, 15,
4.14. Synthesis of 3-phenylpyrido[4,3-b]quinoxalin-1(2H)-
one 10
ꢀ
675e686; (e) Van Rensburg, C. E. J.; Joone, G. K.; Sirgel, F. A.; Matlola, N. M.;
A mixture of 1a (128 mg, 0.5 mmol), DBU (228 mg, 1.5 mmol),
and dry acetonitrile (5 mL) was stirred for 24 h at room tempera-
ture. The reaction mixture was then evaporated to dryness without
heating. The residue was treated with some drops of acetic acid.
After evaporation it was mixed with silica gel and purified by flash
column chromatography on silica gel (2.5ꢂ15 cm) with CH2Cl2 as
the eluent. The yellowish fraction with Rf 0.1 gave 10 (79 mg, 58%).
O’Sullivan, J. F. Chemotheraphy 2000, 46, 43e48; (f) Cimmino, A.; Evidente, A.;
Mathieu, V.; Andolfi, A.; Lefranc, F.; Kornienko, A.; Kiss, R. Nat. Prod. Rep. 2012,
29, 487e501; (g) Gloster, D. F.; Cincotta, L.; Foley, J. W. J. Heterocycl. Chem.
1999, 36, 25e32; (h) Conda-Sheridan, M.; Marler, L.; Park, E.-J.; Kondratyuk, T.
P.; Jermihov, K.; Mesecar, A. D.; Pezzuto, J. M.; Asolkar, R. N.; Fenical, W.;
Cushman, M. J. Med. Chem. 2010, 53, 8688e8699; (i) Borrero, N. V.; Bai, F.;
Perez, C.; Duong, B. Q.; Rocca, J. R.; Jin, S.; Huigens, R. W. Org. Biomol. Chem.
2014, 12, 881e886.
2. Tyaglivy, A. S.; Gulevskaya, A. V.; Pozharskii, A. F.; Askalepova, O. I. Tetrahedron
2013, 69, 9804e9812.
3. (a) Moustafa, O. S.; Badr, M. Z. A.; Kamel, E. M. Pharmazie 2000, 55, 896e899;
(b) Carlier, L.; Baron, M.; Chamayou, A.; Couarraze, G. Tetrahedron Lett. 2011,
4686e4689.
4. Bordwell pKa table (acidity in DMSO) (http://www.chem.wisc.edu/areas/reich/
pkatable/).
5. Anisimova, V. A.; Askalepova, O. I.; Bagdasarov, K. N.; Chernov’yants, M. S. Chem.
Heterocycl. Compd. 1988, 24, 281e284.
6. Gulevskaya, A. V.; Nguyen, H. T. L.; Tyaglivy, A. S.; Pozharskii, A. F. Tetrahedron
2012, 68, 488e498.
Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic
Research (grant no. 14-03-00032-a) for financial support of this
research. We also thank Drs. Anna Tkachuk and Oleg Burov for
technical assistance.
_
€
7. (a) Meusel, M.; Ambrozak, A.; Hecker, T. K.; Gutschow, M. J. Org. Chem. 2002, 68,
Supplementary data
_
€
4684e4692; (b) Ambrozak, A.; Gutschow, M. J. Heterocycl. Chem. 2006, 43,
807e811; (c) Krasnov, K. A.; Kartsev, V. G.; Khrustalev, V. N. Heterocycles 2007, 71,
13e18.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.05.023.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
8. Astruc, D.; Djankovitch, L.; Aranzaes, J. R. ARKIVOC 2006, iv, 173e188.